This proposal will focus on the consequences of, and possible treatments for brain dysfunction in young children with T1 diabetes (T1D). Animal and human research data suggest that both hypo- and hyper-glycemia can be deleterious to brain development, structure and function, with specific brain regions and neural circuits (e.g., fronto-parietal) appearing to be especially vulnerable. In particular, chronic hyperglycemia can affect white matter (WM) volume, myelin glycosylation and specific neurocognitive metrics. However, tight glycemic control in young children with T1D has been limited by risk of hypoglycemia and consequent cognitive impairment. We have compelling new data on brain and cognition differences between 4-9 y/o children with T1D and nondiabetic controls; differences that are strongly associated with hyperglycemia. These results raise important questions about the short- and long-term trajectory of brain development in childhood T1D, pathogenic mechanisms, and the possible impact of targeted interventions. Many of these questions will be addressed with state-of-the-art research methods in this multicenter RO1 in 2 distinct, yet complimentary protocols. Protocol #1 is a longitudinal, natural history study in a large cohort of very young children with T1D and controls for whom we have multi-modal MRI and neurocognitive data at baseline and 18 months. Our aims are to determine: 1) if abnormalities in total and regional GM and WM volumes and WM microstructure change over time, and whether changes are associated with measures of glycemic control; 2) if subjects with T1D show abnormalities in blood oxygen level dependent functional MRI activation of fronto-parietal networks associated with visual-spatial working memory and response inhibition, and if are there abnormalities in functional connectivity of resting state networks; 3) if there are longitudinal changes in normalized scores for IQ, executive, visual-spatial and memory functions in the T1D group, and whether changes are associated with measures of glycemic control. Unsedated structural MRI, DTI and fMRI will be performed twice 2 years apart, using identical 3T scanners, along with age-appropriate neurocognitive testing, and continuous glucose monitoring quarterly. Project #2 is an exploratory study -planned to start in year 3 using children who complete protocol #1 and are >10yrs. Our aim is to determine if substantial tightening of glycemic control overnight and more scrupulous avoidance of nocturnal hypoglycemia using nighttime closed loop (CL) devices for 3 months: (a) alters total and regional GM and WM volumes and WM microstructure as well as task-related and resting- state BOLD activation; and, b) improves specific neurocognitive metrics reflecting vulnerable neural circuits in T1D compared to standard treatment. Our highly qualified group of investigators has a well-established infrastructure, research tools and track record of productivity to successfully perform these studies. This innovative proposal will considerably expand our knowledge on the trajectories of brain and cognitive development in very young children with T1D, an area not well studied and of great contemporary importance.